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Deubiquitinase Activities Required for Hepatocyte Growth Factor-Induced Scattering of Epithelial Cells

The scattering response of epithelial cells to activation of the Met receptor tyrosine kinase represents one facet of an “invasive growth” program [1, 2]. It is a complex event that incorporates loss of cell-cell adhesion, morphological changes, and cell motility. Ubiquitination is a reversible post...

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Detalles Bibliográficos
Autores principales: Buus, Richard, Faronato, Monica, Hammond, Dean E., Urbé, Sylvie, Clague, Michael J.
Formato: Texto
Lenguaje:English
Publicado: Cell Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764384/
https://www.ncbi.nlm.nih.gov/pubmed/19699092
http://dx.doi.org/10.1016/j.cub.2009.07.040
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author Buus, Richard
Faronato, Monica
Hammond, Dean E.
Urbé, Sylvie
Clague, Michael J.
author_facet Buus, Richard
Faronato, Monica
Hammond, Dean E.
Urbé, Sylvie
Clague, Michael J.
author_sort Buus, Richard
collection PubMed
description The scattering response of epithelial cells to activation of the Met receptor tyrosine kinase represents one facet of an “invasive growth” program [1, 2]. It is a complex event that incorporates loss of cell-cell adhesion, morphological changes, and cell motility. Ubiquitination is a reversible posttranslational modification that may target proteins for degradation or coordinate signal transduction pathways [3, 4]. There are ∼79 active deubiquitinating enzymes (DUBs) predicted in the human genome [5, 6]. Here, via a small interfering RNA (siRNA) library approach, we have identified 12 DUBs that are necessary for aspects of the hepatocyte growth factor (HGF)-dependent scattering response of A549 cells. Different phenotypes are evident that range from full loss of scattering, similar to receptor knockdown (e.g., USP30, USP33, USP47), to loss of cell-cell contacts even in the absence of HGF but defective motility (e.g., USP3, ATXN3L). The knockdowns do not incur defective receptor, phosphatidylinositol 3-kinase, or MAP kinase activation. Our data suggest widespread involvement of the ubiquitin system at multiple stages of the Met activation response, implying significant crosstalk with phosphorylation-based transduction pathways. Development of small-molecule inhibitors of particular DUBs may offer a therapeutic approach to contain metastasis.
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spelling pubmed-27643842009-10-23 Deubiquitinase Activities Required for Hepatocyte Growth Factor-Induced Scattering of Epithelial Cells Buus, Richard Faronato, Monica Hammond, Dean E. Urbé, Sylvie Clague, Michael J. Curr Biol Report The scattering response of epithelial cells to activation of the Met receptor tyrosine kinase represents one facet of an “invasive growth” program [1, 2]. It is a complex event that incorporates loss of cell-cell adhesion, morphological changes, and cell motility. Ubiquitination is a reversible posttranslational modification that may target proteins for degradation or coordinate signal transduction pathways [3, 4]. There are ∼79 active deubiquitinating enzymes (DUBs) predicted in the human genome [5, 6]. Here, via a small interfering RNA (siRNA) library approach, we have identified 12 DUBs that are necessary for aspects of the hepatocyte growth factor (HGF)-dependent scattering response of A549 cells. Different phenotypes are evident that range from full loss of scattering, similar to receptor knockdown (e.g., USP30, USP33, USP47), to loss of cell-cell contacts even in the absence of HGF but defective motility (e.g., USP3, ATXN3L). The knockdowns do not incur defective receptor, phosphatidylinositol 3-kinase, or MAP kinase activation. Our data suggest widespread involvement of the ubiquitin system at multiple stages of the Met activation response, implying significant crosstalk with phosphorylation-based transduction pathways. Development of small-molecule inhibitors of particular DUBs may offer a therapeutic approach to contain metastasis. Cell Press 2009-09-15 /pmc/articles/PMC2764384/ /pubmed/19699092 http://dx.doi.org/10.1016/j.cub.2009.07.040 Text en © 2009 ELL & Excerpta Medica. https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license
spellingShingle Report
Buus, Richard
Faronato, Monica
Hammond, Dean E.
Urbé, Sylvie
Clague, Michael J.
Deubiquitinase Activities Required for Hepatocyte Growth Factor-Induced Scattering of Epithelial Cells
title Deubiquitinase Activities Required for Hepatocyte Growth Factor-Induced Scattering of Epithelial Cells
title_full Deubiquitinase Activities Required for Hepatocyte Growth Factor-Induced Scattering of Epithelial Cells
title_fullStr Deubiquitinase Activities Required for Hepatocyte Growth Factor-Induced Scattering of Epithelial Cells
title_full_unstemmed Deubiquitinase Activities Required for Hepatocyte Growth Factor-Induced Scattering of Epithelial Cells
title_short Deubiquitinase Activities Required for Hepatocyte Growth Factor-Induced Scattering of Epithelial Cells
title_sort deubiquitinase activities required for hepatocyte growth factor-induced scattering of epithelial cells
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764384/
https://www.ncbi.nlm.nih.gov/pubmed/19699092
http://dx.doi.org/10.1016/j.cub.2009.07.040
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